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Organische Chemie I - Prof. Dr. Rainer Schobert

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Macrolide Antibiotics

A review commissioned by the UK government in 2014 forecasts that infections caused by drug resistant microorganisms will lead to more deaths than cancer by 2050 if further action is not taken. The WHO set up a list of priority for classes of antibiotics to be further developed with the utmost urgency. The highest ranking classes were fluoroquinolones, cephalosporins, and macrolides.
Over the last decades we synthesised natural macrolide antibiotics with ring sizes ranging from 11 to 22, e.g. grahamimycin A1, norpyrenophorin and A26771B.
In a current project we develop new macrolide antibiotics that overcome the structural limitations of the natural lead compounds and so may outwit the defence strategies of resistant bacteria such as mutation of binding sites, reduced permeability, and increased efflux. Their synthesis follows a modular sugar−based approach: carbon backbone, stereocentres, and OH−groups originate from a freely selectable sugar which is extended by a hydroxy−terminated spacer of varying length and then added to ylide Ph3PCCO. The resulting ω−hemiacetal−esterylide undergoes a Wittig−type macrocyclisation. The attachment of a second sugar at an arbitrary position then leads to chimeric macrolides with a maximum of structural flexibility. This concept was sucessfully applied to the synthesis of natural chloriolide and chimeric sugar derivatives thereof.
Based on docking studies, macrolides are to be synthesised that bear sugars and affinity groups (OH, carboxylates, p−p−stackers) optimised for attractive interaction with the binding cavity of the bacterial ribosome. This may include ribosomal nucleotides and even amino acid residues that are not normally engaged by natural macrolides and which are thus not prone to resistance−related mutational exchange. A good deal of these modifications will also increase the hydrophilicity of the resulting macrolides as well as the numbers of hydrogen bond donors and acceptors. These physico−chemical properties are typical of antibiotics active against gram−negative bacteria.

Grahamimycin A1 Tetrahedron Lett, 1985, 6587
Norpyrenophorin Angew Chem, 97, 1985, 785
A26771B Angew Chem, 97, 1985, 785
Chloriolide J Org Chem, 79, 2014, 4038

Verantwortlich für die Redaktion: André Wetzel

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